Abstract
The co-localization of Cluster-of-Differentiation-44 protein (CD44) and cytoplasmic adaptors in specific membrane environments is crucial for cell adhesion and migration. The process is controlled by two different pathways: On the one hand palmitoylation keeps CD44 in lipid raft domains and disables the linking to the cytoplasmic adaptor, whereas on the other hand, the presence of phosphatidylinositol-4,5-biphosphate (PIP2) lipids accelerates the formation of the CD44-adaptor complex. The molecular mechanism explaining how CD44 is migrating into and out of the lipid raft domains and its dependence on both palmitoylations and the presence of PIP2 remains, however, elusive. In this study, we performed extensive molecular dynamics simulations to study the raft affinity and translocation of CD44 in phase separated model membranes as well as more realistic plasma membrane environments. We observe a delicate balance between the influence of the palmitoylations and the presence of PIP2 lipids: whereas the palmitoylations of CD44 increases the affinity for raft domains, PIP2 lipids have the opposite effect. Additionally, we studied the association between CD44 and the membrane adaptor FERM in dependence of these factors. We find that the presence of PIP2 lipids allows CD44 and FERM to associate in an experimentally observed binding mode whereas the highly palmitoylated species shows no binding affinity. Together, our results shed light on the sophisticated mechanism on how membrane translocation and peripheral protein association can be controlled by both protein modifications and membrane composition.
Highlights
The Cluster-of-Differentiation-44 protein (CD44) is a versatile molecule that is involved in a variety of cellular processes, including inflammation, hematopoiesis, cell migration and cancer invasiveness [1,2,3]
To reveal the preferred partitioning of CD44 between raft and non-raft membrane domains, we simulated a membrane composed of 40%dipalmitoyl-phosphatidylcholine (DPPC)/40% dilinoleoyl-phosphatidylcholine (DLiPC)/20%cholesterol (CHOL) which rapidly segregates into two subdomains (Fig 1C), as observed previously [25]
Simulations including a single copy of the wild-type (WT) of CD44 in the membrane reveal that CD44-WT prefers to reside in the DLiPC-enriched liquid-disordered domain (Ld) phase, as apparent from a snapshot at the end of the simulation as well as analysis of the contact frequency distribution of the protein with the two lipid types (Fig 2A)
Summary
The Cluster-of-Differentiation-44 protein (CD44) is a versatile molecule that is involved in a variety of cellular processes, including inflammation, hematopoiesis, cell migration and cancer invasiveness [1,2,3]. The ED can undergo different modifications, like hyaluronic acid binding and proteolytic shedding, which are regulated by the localization of the TMD and possible self-assembly. The localization of CD44 into the ordered, “lipid raft” [4,5], microdomains can suppress the binding of the CT to cytoskeleton adaptors of the Ezrin, Radixin and Moesin (ERM) family, which act as regulators of cell motility and differentiation [6,7]. The palmitoylations on CD44 control the association/dissociation switching of CD44 and Radixin, a process, that has been identified in tumor cell migration and proliferation [9]
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